title: Valine, the branched-chain amino acid, suppresses hepatitis C virus RNA replication but promotes infectious particle formation.
abstract: OBJECTIVE
  Concentrations of the branched-chain amino acid (BCAA) in the serum of patients with liver cirrhosis correlate with their liver function. Oral administration of BCAA can ameliorate hypoalbuminemia and hepatic encephalopathy. In this study, we aim to clarify the role of BCAA in regulating the replication of the hepatitis C virus (HCV).
  
  
  METHODS
  HCV sub-genomic replicon cells, genome-length replicon cells, and cells infected with cell culture-infectious HCV (HCVcc) were cultured in media supplemented with various concentrations of BCAA, followed by evaluation of the replicon or HCV abundance.
  
  
  RESULTS
  BCAA was capable of suppressing the HCV replicon in a dose-dependent manner and the effect was independent of the mTOR pathway. Of the three BCAAs, valine was identified as being responsible for suppressing the HCV replicon. Surprisingly, an abundance of HJ3-5(YH/QL), an HCVcc, in Huh7 cells was augmented by BCAA supplementation. In contrast, BCAA suppressed an abundance of HJ3-5(wild), an HCVcc that cannot assemble virus particle in Huh7 cells. Internal ribosome entry site of HCV was shown to be a target of BCAA. Single-cycle virus production assays using Huh7-25 cells, which lacked CD81 expression, revealed that BCAA, especially valine, promoted infectious virus particle formation with minimal effect on virus secretion. Thus, BCAA was found to have two opposing effects on HCV production: suppression of the HCV genome RNA replication and promotion of infectious virus formation.
  
  
  CONCLUSIONS
  BCAA accelerates HCV production through promotion of infectious virus formation in infected cells despite its suppressive effect on HCV genome replication.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ishida
authors.forename: Takanobu
authors.initials: T
authors.lastname: Kato
authors.forename: Kenji
authors.initials: K
authors.lastname: Takehana
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hosui
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Nawa
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kodama
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shimizu
authors.forename: Hayato
authors.initials: H
authors.lastname: Hikita
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kanto
authors.forename: Norio
authors.initials: N
authors.lastname: Hayashi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
mesh_terms: D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism*; D012093:Replicon / Q000235:genetics; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014633:Valine / Q000494:pharmacology*; D014771:Virion / Q000187:drug effects / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D012367:RNA, Viral; D050791:STAT Transcription Factors; C546842:MTOR protein, human; D053612:Janus Kinases; D058570:TOR Serine-Threonine Kinases; D014633:Valine
keywords: Branched-chain amino acid; Hepatitis C virus; IRES activity; Infectious virus production; JAK/STAT pathway; Mammalian target of rapamycin